INTRODUCTION

Recently the armamentarium (i.e., the medicines, equipment and techniques available to a
medical practitioner) pharmaceuticals almost completely comprised small organic molecules,
the majority of which were synthesized in the laboratory

Steady advances in cellular biology and in biotechnology have allowed scientists to create
new therapeutic entities mimicking endogenous bioactive substances

These new products include proteins, peptides, monoclonal antibodies, oligonucleotides,
vaccines against microbiological and non-microbiological diseases, and gene therapy
treatments

Pharmacists need to understand the pharmacokinetics and pharmacodynamics of these
therapeutic products of biotechnology, which will constitute an ever-increasing proportion of
the medications that they will be called on to provide for patients.

PROTEINS and PEPTIDES

Proteins- are the large organic compounds made of amino acids arranged in a linear chain
and joined together by peptide bonds.

Protein > 50 amino acids

Peptides- are short polymers formed from the linking in a defined order of amino acids.

Peptides< 50 amino acids

• The size range of these compounds that are in use ranges from 1 kDa to 320 kDa
• Smallest substance is oxytocin, a 9-amino-acid peptide which is produced by chemical

synthesis
• Largest compound is the antihemophilic factor, a large glycoprotein produced by

recombinant DNA technology

LIST OF PROTEIN and PEPTIDE DRUGS

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ROUTE OF ADMINISTRATION

✓ Proteins and peptides of smaller size can only be administered orally. This is because
large peptides and proteins are subject to degradation and inactivation in the
gastrointestinal tract. There by systemic bioavailability will be negligible.
Desmopressin (1.18 kDa)

✓ Becaplermin(25 kDa) is a drug that is administered topically as its site of action is on
the surface of the skin, even though there are no protein drugs that can be
administered transdermally due to their large molecular weight and thus interfering
with systemic absorption.

✓ They can also be administered through nasal route, for example: DNase (Pulmozyme).
It is an enzyme used to break down thick mucus secretions in the respiratory tracts of
cystic fibrosis patients. But for an inhaled protein that requires systemic absorption in
order to exert its therapeutic effect is the inhalable form of human insulin, Exubera
which have been showed better disposition and efficacy were comparable to those of
subcutaneously administered insulin and also its absorption was somewhat faster

✓ The majority of these drugs are administered parenterally, either subcutaneously,
intramuscularly, or systemically by intravenous injection or infusion

Many of the drugs have very high systemic absorption from subcutaneous and intramuscular
dosage forms.

PHARMACOKINETICS & PHARMACODYNAMICS OF PROTEIN & PEPTIDE DRUGS

• Apparent volumes of distribution of these proteins and peptides are relatively small
and roughly inversely correlated with their molecular weights.

• However, irrespective of the value of the distribution volume, each protein is
distributed to the tissue containing receptors for its therapeutic activity in an amount
adequate to elicit effect. This specific distribution, though most important for effect,
is often of too small a magnitude to affect the value of the overall volume of
distribution.

• For proteins, the total volume of distribution at steady state is usually not more than
twice the initial volume of distribution.

• Pegylation often decreases the volume of distribution of a protein drug.
• Most of the protein and peptide drugs have short elimination half-lives, as recorded

in intravenous studies. However, when these drugs are administered by subcutaneous
or intramuscular injection, delayed absorption causes plasma drug levels to remain
high for an appreciable period of time.

• Proteins and peptide drugs are glycosylated or pegylated to increase their half-life.
• The desired therapeutic and pharmacokinetics of these drugs can be achieved by

bioengineering such as by glycosylation, deglycosylation, pegylation, cyclization, or
conjugation, etc.,

• The site and mechanism of elimination may be determined by charge, oil/water
partition coefficient, the presence of sugars or other functional groups associated with
the protein and to a large extent by molecular weight.

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Elimination through kidney:

–Proteins that are small enough to be filtered by the glomerulus in the kidney (<60 kDa) may
either be absorbed by endocytosis into proximal tubule cells followed by lysosomal
degradation (bradykinin) or may be metabolized by enzymes at the luminal brush border
membrane.

–Proteins and peptides like insulin, parathyroid harmone and vasopressin are degraded by
peritubular receptors.

–Receptor-mediated endocytosis in the kidney is also an important mechanism of
degradation of proteins that are too large to be filtered by the glomerulus.

Degradation in liver by intracellular catabolism:

–small polypepties (<1kDa): are transported to these cells by passive diffusion or carrier
mediated uptake

–moderate size proteins (50-200kDa): receptor mediated endocytosis

Even though insulin has molecular weight of 5.8kDa, which is below the mentioned range,
insulin is eliminated to a considerable extent by receptor-mediated endocytosis in the liver.

–largest proteins (200-400kDa): are opsonized by immunoglobulins followed by phagocytosis

–protein complexes (>400kDa): eliminated by phagocytosis

• For certain proteins, elimination through receptor mediated endocytosis occurs
outside the liver. For example:

–Granulocyte colony stimulating factor (GCSF) binds to receptor in bone marrow that can
eliminate this protein by saturable process

–Macrophage colony stimulating factor (MCSF) is eliminated in part by binding to
macrophages

• Elimination of these drugs may be complex process with dose-dependent, saturable
pharmacokinetics.

• Plasma levels of the protein drugs may infact, correlate poorly with therapeutic effect.
The drug may be cleared from blood not because of an elimination process but instead
because it is taken up by a receptor where it may reside for some time exerting its
therapeutic effect.

• The curve of therapeutic effect as a function of time may be temporarily displaced
with respect to the curve of plasma drug level over time, requiring the use of indirect
PK and PD modelling.

REFERENCE: Basic Pharmacokinetics. Sunil S Jambhekar and Philip J Breen. Second edition
2012. Published:Pharmaceutical Press. Pg no.413-426.

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